Pancreatic cholesterol esterase (CEase) is a lipolytic enzyme that catalyzes the hydrolysis of cholesteryl esters, phospholipids and triacylglycerols in the intestinal tract. The enzyme may play a role in the absorption of dietary cholesterol across the intestinal mucosa and eventually into the bloodstream.
Since CEase is required for the absorption of dietary fatty acids, dietary cholesterol, cholesterol esters and bile derived cholesterol into the bloodstream, CEase inhibitors may serve as hypolipidemic, hypocholesterolaemic and hypocaloric agents. Such treatments would be useful in the treatment of hypercholesterolaemia and obesity, health problems that afflict one-third of Americans. It is also a known risk factor in diabetes, arteriosclerosis, atherosclerosis and other life threatening diseases.
U.S. Pat. No. 4,189,438 discloses that a natural product, esterastin, a lactone, inhibits cholesterol esterase and other esterases.
U.S. Pat. No. 4,202,824 discloses that derivatives of esterastin also are active as inhibitors of cholesterol esterase.
U.S. Pat. No. 5,093,371 discloses naphthyl ketone inhibitors of cholesterol esterase.
The prevention of absorption of cholesterol has been largely unexploited as a pharmacological method of treatment of arteriosclerosis. One way of preventing absorption of cholesterol is to cover the walls of the intestinal tract with something which prevents absorption of cholesterol through the intestinal mucosa. This, however, is difficult and not practical because it inhibits the normal digestive process. A far more effective approach would be to develop CEase inhibitors with demonstrated capability of blocking cholesterol absorption. These inhibitors could then be introduced into the alimentary tract through appropriate delivery systems where it would then function to block cholesterol absorption.
This invention is predicated upon the discovery of certain novel CEase inhibitors which successfully block cholesterol absorption, to their use for decreasing the absorption of dietary cholesterol and other fats, and to a pharmaceutical composition comprising the active compound.